Compounds that affect neuronal excitability through modulation of specific ionotropic receptors
Neurosteroids, also known as neuroactive steroids, are
endogenous or exogenous
steroids that rapidly alter
neuronal excitability through interaction with
ligand-gated ion channels and other
cell surface receptors.[1][2] The term neurosteroid was coined by the French
physiologistÉtienne-Émile Baulieu and refers to steroids synthesized in the brain.[3][4] The term, neuroactive steroid refers to steroids that can be synthesized in the brain, or are synthesized by an
endocrine gland, that then reach the brain through the bloodstream and have effects on brain function.[5] The term neuroactive steroids was first coined in 1992 by Steven Paul and Robert Purdy. In addition to their actions on neuronal membrane receptors, some of these steroids may also exert effects on
gene expression via nuclear
steroid hormone receptors. Neurosteroids have a wide range of potential clinical applications from
sedation to treatment of
epilepsy[6] and
traumatic brain injury.[7][8]Ganaxolone, a synthetic analog of the endogenous neurosteroid
allopregnanolone, is under investigation for the treatment of epilepsy.[9]
Certain other endogenous steroids, such as
pregnenolone,[21]progesterone,[22][23]estradiol,[5] and
corticosterone are also neurosteroids. However, unlike those listed above, these neurosteroids do not modulate the GABAA or NMDA receptors, and instead affect various other cell surface receptors and non-genomic targets. Also, many endogenous steroids, including pregnenolone, progesterone, corticosterone,
deoxycorticosterone, DHEA, and
testosterone, are
metabolized into (other) neurosteroids, effectively functioning as so-called proneurosteroids.
Biosynthesis
Neurosteroids are synthesized from
cholesterol, which is converted into pregnenolone and then into all other endogenous steroids. Neurosteroids are produced in the brain after local synthesis or by conversion of peripherally-derived adrenal steroids or gonadal steroids. They accumulate especially in myelinating glial cells, from cholesterol or steroidal precursors imported from peripheral sources.[24][25]5α-reductase type I and
3α-hydroxysteroid dehydrogenase are involved in the biosynthesis of inhibitory neurosteroids, while
3β-hydroxysteroid dehydrogenase and
hydroxysteroid sulfotransferases are involved in excitatory neurosteroid production.[3]
Acute stress elevates the levels of inhibitory neurosteroids like allopregnanolone, and these neurosteroids are known to counteract many of the effects of stress.[32] This is similar to the case of
endorphins, which are released in response to stress and physical pain and counteract the negative subjective effects of such states. As such, it has been suggested that one of the biological functions of these
neuromodulators may be to help maintain emotional
homeostasis.[28][33]Chronic stress has been associated with diminished levels of allopregnanolone and altered allopregnanolone stress responsivity,
psychiatric disorders, and
hypothalamic-pituitary-adrenal axis dysregulation.[31][32]
Elevated levels of inhibitory neurosteroids, namely allopregnanolone, can produce paradoxical effects, such as
negative mood,
anxiety,
irritability, and
aggression.[39][40][41][42] This appears to be because these neurosteroids, like other positive allosteric modulators of the GABAA receptor such as the
benzodiazepines,
barbiturates, and
ethanol,[34][42] possess biphasic, U-shaped actions – moderate levels (in the range of 1.5–2 nM/L total alloprogesterone, which are approximately equivalent to
luteal phase levels) inhibit the activity of the GABAA receptor, while lower and higher concentrations facilitate the activity of the receptor.[40][41]
Several synthetic neurosteroids have been used as
sedatives for the purpose of
general anaesthesia for carrying out surgical procedures. The best known of these are
alphaxolone,
alphadolone,
hydroxydione, and
minaxolone. The first of these to be introduced was hydroxydione, which is the esterified 21-hydroxy derivative of 5β-pregnanedione. Hydroxydione proved to be a useful anaesthetic drug with a good safety profile, but was painful and irritating when injected probably due to poor water solubility. This led to the development of newer neuroactive steroids. The next drug from this family to be marketed was a mixture of alphaxolone and alphadolone, known as
Althesin. This was withdrawn from human use due to rare but serious toxic reactions, but is still used in
veterinary medicine. The next neurosteroid anaesthetic introduced into human medicine was the newer drug minaxolone, which is around three times more potent than althesin and retains the favourable safety profile, without the toxicity problems seen with althesin. However this drug was also ultimately withdrawn, not because of problems in clinical use, but because animal studies suggested potential carcinogenicity and since alternative agents were available it was felt that the possible risk outweighed the benefit of keeping the drug on the market.
Ganaxolone
The neurosteroid
ganaxolone, an analog of the progesterone metabolite allopregnanolone, has been extensively investigated in animal models and is currently in clinical trials for the treatment of
epilepsy. Neurosteroids, including ganaxolone have a broad spectrum of activity in animal models.[46] They may have advantages over other GABAA receptor modulators, notably benzodiazepines, in that tolerance does not appear to occur with extended use.[47][48]
A randomized, placebo controlled, 10-week phase 2 clinical trial of orally administered ganaxolone in adults with partial onset seizure demonstrated that the treatment is safe, well tolerated and efficacious.[9] The drug continued to demonstrate efficacy in a 104-week open label extension. Data from non-clinical studies suggest that ganaxolone may have low risk for use in pregnancy. In addition to use in the treatment of epilepsy, the drug has potential in the treatment of a broad range of neurological and psychiatric conditions. Proof-of-concept studies are currently underway in posttraumatic stress disorder and fragile X syndrome. Ganaxolone was approved for medical use in the United States in March 2022.
Catamenial epilepsy
Researchers have suggested the use of so-called "neurosteroid replacement therapy" as a way of treating
catamenial epilepsy with neuroactive steroids such as ganaxolone during the period of the
menstrual cycle when
seizure frequency increases.[6]Micronized progesterone, which behaves reliably as a
prodrug to allopregnanolone, has been suggested as a treatment for catamenial epilepsy in the same manner.[49]
Certain
antidepressant drugs such as
fluoxetine and
fluvoxamine, which are generally thought to affect depression by acting as
selective serotonin reuptake inhibitors (SSRIs), have also been found to normalize the levels of certain neurosteroids (which are frequently deficient in depressed patients) at doses that are inactive in affecting the
reuptake of
serotonin. This suggests that other actions involving neurosteroids may also be at play in the effectiveness of these drugs against depression.[56][57]
Benzodiazepines may influence neurosteroid metabolism by virtue of their actions on
translocator protein (TSPO; "peripheral benzodiazepine receptor").[62] The
pharmacological actions of benzodiazepines at the GABAA receptor are similar to those of
neurosteroids. Factors which affect the ability of individual benzodiazepines to alter neurosteroid levels may depend upon whether the individual benzodiazepine drug interacts with TSPO. Some benzodiazepines may also inhibit neurosteroidogenic enzymes reducing neurosteroid synthesis.[63]
^Rougé-Pont F, Mayo W, Marinelli M, Gingras M, Le Moal M, Piazza PV (July 2002). "The neurosteroid allopregnanolone increases dopamine release and dopaminergic response to morphine in the rat nucleus accumbens". The European Journal of Neuroscience. 16 (1): 169–73.
doi:
10.1046/j.1460-9568.2002.02084.x.
PMID12153544.
S2CID9953445.
^Terán-Pérez G, Arana-Lechuga Y, Esqueda-León E, Santana-Miranda R, Rojas-Zamorano JÁ, Velázquez Moctezuma J (October 2012). "Steroid hormones and sleep regulation". Mini Reviews in Medicinal Chemistry. 12 (11): 1040–8.
doi:
10.2174/138955712802762167.
PMID23092405.
^Patte-Mensah C, Meyer L, Taleb O, Mensah-Nyagan AG (February 2014). "Potential role of allopregnanolone for a safe and effective therapy of neuropathic pain". Progress in Neurobiology. 113: 70–8.
doi:
10.1016/j.pneurobio.2013.07.004.
PMID23948490.
S2CID207407077.
^Marx CE, Bradford DW, Hamer RM, Naylor JC, Allen TB, Lieberman JA, Strauss JL, Kilts JD (September 2011). "Pregnenolone as a novel therapeutic candidate in schizophrenia: emerging preclinical and clinical evidence". Neuroscience. 191: 78–90.
doi:
10.1016/j.neuroscience.2011.06.076.
PMID21756978.
S2CID26396652.
^Baulieu E, Schumacher M (2000). "Progesterone as a neuroactive neurosteroid, with special reference to the effect of progesterone on myelination". Steroids. 65 (10–11): 605–12.
doi:
10.1016/s0039-128x(00)00173-2.
PMID11108866.
S2CID14952168.
^
abBali A, Jaggi AS (January 2014). "Multifunctional aspects of allopregnanolone in stress and related disorders". Progress in Neuro-Psychopharmacology & Biological Psychiatry. 48: 64–78.
doi:
10.1016/j.pnpbp.2013.09.005.
PMID24044974.
S2CID21399549.
^Andréen L, Sundström-Poromaa I, Bixo M, Nyberg S, Bäckström T (August 2006). "Allopregnanolone concentration and mood--a bimodal association in postmenopausal women treated with oral progesterone". Psychopharmacology. 187 (2): 209–21.
doi:
10.1007/s00213-006-0417-0.
PMID16724185.
S2CID1933116.
^
abBäckström T, Haage D, Löfgren M, Johansson IM, Strömberg J, Nyberg S, Andréen L, Ossewaarde L, van Wingen GA, Turkmen S, Bengtsson SK (September 2011). "Paradoxical effects of GABA-A modulators may explain sex steroid induced negative mood symptoms in some persons". Neuroscience. 191: 46–54.
doi:
10.1016/j.neuroscience.2011.03.061.
PMID21600269.
S2CID38928854.
^
abAndréen L, Nyberg S, Turkmen S, van Wingen G, Fernández G, Bäckström T (September 2009). "Sex steroid induced negative mood may be explained by the paradoxical effect mediated by GABAA modulators". Psychoneuroendocrinology. 34 (8): 1121–32.
doi:
10.1016/j.psyneuen.2009.02.003.
PMID19272715.
S2CID22259026.
^
abBäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G, Savic I, Strömberg J, Timby E, van Broekhoven F, van Wingen G (February 2014). "Allopregnanolone and mood disorders". Progress in Neurobiology. 113: 88–94.
doi:
10.1016/j.pneurobio.2013.07.005.
PMID23978486.
S2CID207407084.
^Maurice T, Urani A, Phan VL, Romieu P (2001). "The interaction between neuroactive steroids and the sigma1 receptor function: behavioral consequences and therapeutic opportunities". Brain Res. Brain Res. Rev. 37 (1–3): 116–32.
doi:
10.1016/s0165-0173(01)00112-6.
PMID11744080.
S2CID44931783.
^
abcdeTakebayashi M, Hayashi T, Su TP (2004). "A perspective on the new mechanism of antidepressants: neuritogenesis through sigma-1 receptors". Pharmacopsychiatry. 37 (Suppl 3): S208–13.
doi:
10.1055/s-2004-832679.
PMID15547787.
S2CID260243232.
^Rogawski MA, Reddy DS, 2004. Neurosteroids: endogenous modulators of seizure susceptibility. In: Rho, J.M., Sankar, R., Cavazos, J. (Eds.), Epilepsy: Scientific Foundations of Clinical Practice. Marcel Dekker, New York, 2004;319-355.
^Kokate TG, Yamaguchi S, Pannell LK, Rajamani U, Carroll DM, Grossman AB, Rogawski MA (November 1998). "Lack of anticonvulsant tolerance to the neuroactive steroid pregnanolone in mice". The Journal of Pharmacology and Experimental Therapeutics. 287 (2): 553–8.
PMID9808680.
^Reddy DS, Rogawski MA (December 2000). "Chronic treatment with the neuroactive steroid ganaxolone in the rat induces anticonvulsant tolerance to diazepam but not to itself". The Journal of Pharmacology and Experimental Therapeutics. 295 (3): 1241–8.
PMID11082461.
^Pinna G, Costa E, Guidotti A (24 January 2006). "Fluoxetine and norfluoxetine stereospecifically and selectively increase brain neurosteroid content at doses that are inactive on 5-HT reuptake". Psychopharmacology. 186 (3): 362–72.
doi:
10.1007/s00213-005-0213-2.
PMID16432684.
S2CID7799814.
^Schüle C, Romeo E, Uzunov DP, Eser D, di Michele F, Baghai TC, Pasini A, Schwarz M, Kempter H, Rupprecht R (March 2006). "Influence of mirtazapine on plasma concentrations of neuroactive steroids in major depression and on 3alpha-hydroxysteroid dehydrogenase activity". Mol. Psychiatry. 11 (3): 261–72.
doi:
10.1038/sj.mp.4001782.
PMID16344854.
S2CID21473462.
Melcangi RC, Celotti F, Martini L (March 1994). "Progesterone 5-alpha-reduction in neuronal and in different types of glial cell cultures: type 1 and 2 astrocytes and oligodendrocytes". Brain Research. 639 (2): 202–6.
doi:
10.1016/0006-8993(94)91731-0.
PMID8205473.
S2CID37105244.